As a soluble cellulose derivative, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose and the like are known. Among them, carboxymethyl cellulose having a carboxymethyl group introduced thereinto (hereinafter, carboxymethyl cellulose means sodium carboxymethyl cellulose in accordance with general appellation) is a representative one, and is widely used in a food field or as e.g. a water-absorptive material utilizing its viscoelasticity, and its application extends to a medical field.
With respect to application of carboxymethyl cellulose to a medical field, a report has been made such that an effect of a carboxymethyl cellulose aqueous solution or one obtained by drying and molding it, as an adhesion preventive, has been confirmed, however, no adequate effect has been obtained (American Journal of Surgery, Vol. 169, 154-159 (1995)). JP-A-1-301624 and U.S. Pat. No. 5,906,997 disclose an adhesion preventive comprising a carboxymethyl cellulose composition using a chemical cross-linking agent or a chemical modifying agent, and an adhesion preventive in a film-form, which is a composition obtained by modifying hyaluronic acid and carboxymethyl cellulose with a carbodiimide, developed based on JP-A-5-508161 and JP-A-6-508169, “Seprafilm” (manufactured by Genzyme Corporation) is commercially available.
However, no example has been found wherein a carboxymethyl cellulose having been made hardly soluble in water, which is substantially unmodified, is used for an adhesion preventive.
With respect to a wound dressing, JP-A-11-322615 discloses a wound-curing agent comprising carboxymethyl cellulose and fibrin, JP-A-7-109220 discloses a wound-curing agent comprising carboxymethyl cellulose and a disinfectant, and German Patent No. 1397893 discloses a wound-curing agent comprising carboxymethyl cellulose and an anti-inflammatory agent. Further, JP-A-8-505258 and European Patent No. 47647 disclose a wound dressing comprising a crosslinked carboxymethyl cellulose. All of them comprise a soluble carboxymethyl cellulose or carboxymethyl cellulose crosslinked by means of e.g. a chemical cross-linking agent, and a use of carboxymethyl cellulose having been made hardly soluble in water, which is unmodified, as a wound dressing, is not disclosed similar to the case of an adhesion preventive.
On the other hand, as an implant in a form of a block to be used with a purpose of bone repair, for example, JP-A-62-39506 discloses a porous sponge having chitin crosslinked therewith by means of a chemical, JP-A-3-23864 discloses a composite material in a form of a block comprising a collagen sponge and polylactic acid, and JP-A-7-505643 discloses an excellent bone-substituting agent having biocompatibility and bioabsorptivity, comprising a hyaluronate. However, a porous sponge is non-absorptive in the body, whereby it is not completely substituted by the bone, and there are a risk of infection and a risk of the material itself being separated, and further, in a case where collagen is used, there is such a defect that atelocollagen has a slight antigenicity.
Further, a chemical carrier (Pharm. Develop. Tech., Vol. 4, 55-63 (1999)), a cell culture medium (J. M. S.—Pure Appl. Chem., Vol. A33, 1875-1884 (1996)), a polypeptide growth factor-containing gel composition (U.S. Pat. No. 5,705,485) and the like are reported or disclosed, but in all cases, carboxymethyl cellulose to be used is different from that in the present invention.
Conventionally, for example, to improve material characteristics such as viscoelasticity of carboxymethyl cellulose for example, a chemically crosslinked carboxymethyl cellulose by means of glyoxal as disclosed in JP-A-10-251447, a carboxymethyl cellulose gel mixed with multivalent metal ions as disclosed in JP-A-63-37143, a carboxymethyl cellulose gel by means of a bivalent or trivalent metal salt as disclosed in JP-A-7-090121, and a carboxymethyl cellulose gel by addition of a basic aluminum acetate as disclosed in JP-A-11-106561, has been considered. However, to such a modified carboxymethyl cellulose, a chemical cross-linking agent is used or metal ions are added, and a material containing no such material has been desired in view of safety when used as medical products.
As the method to obtain a carboxymethyl cellulose having been made hardly soluble in water, a method of leaving an acidic solution of carboxymethyl cellulose to stand (Encyclopedia of Polymer Science & Technology, Vol. 3, 520-539 (1965)), a method of adding a strong acid to a granular carboxymethyl cellulose in the presence of methyl alcohol or ethyl alcohol (Colloid Polym. Sci., Vol. 267, 226-236 (1989)) and a method of using a strong ionic cation exchange resin (U.S. Pat. No. 2,617,800) may, for example, be mentioned. Further, a method of concentrating an acidic solution of carboxymethyl cellulose by means of ultracentrifugation may also be used. However, in these methods, there are problems in handling properties and time until a carboxymethyl cellulose having been made hardly soluble in water is obtained, yield, and such a problem that it tends to be difficult to form the obtained carboxymethyl cellulose having been made hardly soluble in water into a sheet, film, sponge or tube.
In order to achieve the above objects, the present inventors have conducted extensive studies on physicochemical characteristics of the soluble cellulose derivative itself and its effect on the body. As a result, they have found that a soluble cellulose derivative having been made hardly soluble in water, obtained by an acid treatment, which has conventionally been reported, has a high effect as a tissue-covering medical material such as an adhesion preventive or a wound dressing. Further, they have found that a material produced by a means of freezing and thawing a soluble cellulose derivative aqueous solution under an acidic condition, which has not conventionally been studied, has a fibrous or fill-like fine structure due to an effect of ice crystals formed during freezing. It was clarified that the soluble cellulose derivative having been made hardly soluble in water obtained by freezing and thawing is not only easily formed into a sheet, a film, a sponge or the like, but also easily formed into a sheet, a film, a tube or the like in a uniform form after it is crushed by means of a mixer or supersonic wave, and it has excellent material characteristics as a medical material, as compared with a soluble cellulose derivative having been made hardly soluble in water prepared by an acid treatment which has conventionally been known.
Further, with respect to adaptability in application to the body, candidates which have a controlled solubility which is an important physical property, and which has an extremely high adhesion preventive effect and high adaptability could be found, and the present invention has been accomplished.